Tuesday, August 11, 2015

Four things that Francis Collins learned from sequencing the human genome

I've been doing a bit of research on the human genome in preparation for a book. This led me to an article published in 2003 by Francis Collins, former head of the Human Genome Consortium (Collins, 2003). It's mostly about how he deals with science and religion but there was an interesting description of what he learned from completing the human genome sequence.

Here's what he said ....
We discovered some pretty surprising things in reading out the human genome sequence. Here are four highlights.

1. Humans have fewer genes than expected. My definition of a gene here—because different people use different terminology—is a stretch of DNA that codes for a particular protein. There are probably stretches of DNA that code for RNAs that do not go on to make proteins. That understanding is only now beginning to emerge and may be fairly complicated. But the standard definition of “a segment of DNA that codes for a protein” gives one a surprisingly small number of about 30,000 for the number of human genes. Considering that we’ve been talking about 100,000 genes for the last fifteen years (that’s what most of the textbooks still say), this was a bit of a shock. In fact, some people took it quite personally. I think they were particularly distressed because the gene count for some other simpler organisms had been previously determined. After all, a roundworm has 19,000 genes, and mustard weed has 25,000 genes, and we only have 30,000? Does that seem fair? Even worse, when they decoded the genome of the rice, it looks as if rice has about 55,000 genes. So you need to have more respect for dinner tonight! What does that mean? Surely, an alien coming from outer space looking at a human being and looking at a rice plant would say the human being is biologically more complex. I don’t think there’s much doubt about that. So gene count must not be the whole story. So what is going on?

2. Human genes make more proteins than those of other critters. One of the things going on is that we begin to realize that one gene does not just make one protein in humans and other mammals. On the average, it makes about three, using the phenomenon of alternative splicing to create proteins with different architectures. One is beginning to recover some sense of pride here in our genome, which was briefly under attack, because now we can say, “Well, we don’t have very many genes but boy are they clever genes. Look what they can do!”

3. The male mutation rate is twice that of females. We also discovered that simply by looking at the Y chromosome and comparing it to the rest of the genome—of course, the Y chromosome only passes from fathers to sons, so it only travels through males—you can get a fix on the mutation rate in males compared to females. This was not particularly good news for the boys in this project because it seems that we make mistakes about twice as often as the women do in passing our DNA to the next generation. That means, guys, we have to take responsibility for the majority of genetic disease. It has to start somewhere; the majority of the time, it starts in us. If you are feeling depressed about that, let me also point out we can take credit for the majority of evolutionary progress, which after all is the same phenomenon.

4. “Junk” DNA may not be junk after all. I have been troubled for a long time about the way in which we dismissed about 95% of the genome as being junk because we didn’t know what its function was. We did not think it had one because we had not discovered one yet. I found it quite gratifying to discover that when you have the whole genome in front of you, it is pretty clear that a lot of the stuff we call “junk” has the fingerprints of being a DNA sequence that is actually doing something, at least, judging by the way evolution has treated it. So I think we should probably remove the term “junk” from the genome. At least most of it looks like it may very well have some kind of function.
I don't know if Francis Collins still believes these four things and still believes they were discovered by those who sequenced the human genome. However, I think it's worthwhile for me to give you a slightly different perspective on what I did NOT think were highlights of the human genome sequence.
  1. Number of Genes: I don't question the fact that Francis Collins and many of his colleagues were surprised at the low number of genes in the human genome when the draft sequence first came out. Nor do I question his explanation; namely, hubris. But he should also add lack of knowledge of the scientific literature. Knowledgeable scientists knew that there should be no more than 30,000 genes and, furthermore, the discoveries in developmental biology led them to be quite comfortable with the idea that all complex eukaryotes would have about the same number of genes. I've written about the misconceptions of leading scientists over the number of genes in False History and the Number of Genes and Facts and Myths Concerning the Historical Estimates of the Number of Genes in the Human Genome. It astonishes me that scientists working on the human genome were not aware of the scientific literature on the number of genes in the human genome.

    It also astonishes me that scientists in the 21st century could still have been defining a gene as "a stretch of DNA that codes for a particular protein." I'm gradually becoming aware of the fact that this is/was a common mistake that persists to this day. It means that undergraduate biochemistry and molecular biology lecturers are not doing their job.

    I also written about The Deflated Ego Problem and how human chauvinists are trying to cope with the idea that they may just be animals like all other animals. In that post I outlined seven ways that scientists with deflated egos are going to try and restore humans to top spot in the evolutionary tree [see also: Vertebrate Complexity Is Explained ...]. The seven ways are:
    1. Alternative Splicing
    2. The Abundance of Small RNAs
    3. The Function of Pseudogenes
    4. Transposon
    5. Regulatory Sequences
    6. The Unspecified Anti-Junk Argument
    7. Post-translational Modification
    All of these arguments for human exceptionalism have been trotted out over the past 15 years.

  2. Alternative Splicing: Right on cue! There are two main problems with the idea that alternative splicing is going to assuage your deflated ego. The first is that the logic of the argument is questionable. It only works if alternative splicing is common in humans—giving rise to lots more proteins—and uncommon in those "lower" organisms that we want to be superior to. But the same data that's used to infer alternative splicing in humans also shows multiple transcripts for Drosophila, mouse, and Arabidopsis genes. This argument isn't going to save you unless you invoke special pleading [An Example of Faulty Logic from Cold Spring Harbor].

    The second problem is that alternative splicing is just as spurious as pervasive transcription and transcription factor binding. It's true that you can detect lots of different transcripts from most human genes. Many of them contain different combinations of introns and exons and they start and stop at many locations. The "variants" are almost always extremely rare [The most important rule for publishing a paper on alternative splicing ]. That's consistent with the high error rate of splicing [Splicing Error Rate May Be Close to 1% ]. These are nonfunctional mistakes. There are genuine examples of alternative splicing producing different proteins but these genes make up fewer than 5% of all genes in the human genome and they usually are not unique to humans or mammals.

    The argument that transcripts of most human genes are alternatively spliced does not make any sense on many levels [Two Examples of "Alternative Splicing" and Making Sense in Biology and A Challenge to Fans of Alternative Splicing].

  3. High Mutation Rate in Males: We knew about this long before the human genome sequence was determined. The original discovery is attributed to J.B.S. Haldane in 1947 (see Crow, 1997 for a review). I don't know why Francis Collins didn't know about this before 2000.

  4. “Junk” DNA may not be junk after all: He's wrong about that. We know that about 90% of our genome is junk. Most of us knew that before the human genome sequence was published and the sequence provided solid evidence that we were right. For example, it turned out that half the genome was bits and pieces of defective transposons just as predicted. It turned out that there were only about 30,000 genes, just as expected. It turned out that there were large stretches of highly repetitive DNA, just as expected. It turned out that 20% of the genome consisted of highly variable intron sequences (junk), just as expected. And we soon learned that much of the rest of the genome was not conserved, just as expected.

Collins, F.S. (2003) Faith and the Human Genome. Perspectives on Science and Christian Faith 55: 142-153. [PDF]

Crow, J.F. (1997) The high spontaneous mutation rate: Is it a health risk? Proc. Natl. Acad. Sci. (USA) 94: 8380-8397. [PDF]

68 comments :

  1. From Susumu Ohno's 1972 paper, he cites Muller (1967) and Crow and Kimura (1970) as saying that the upper limit for human gene loci is 3 x 10^4 (30,000). They arrive at this number by estimates of genetic load and deleterious mutation rates.
    http://www.junkdna.com/ohno.html

    I, however, do recall being an undergraduate in genetics in the early 90's and learning that humans may have "more than 100,000 genes" from college-level textbooks.

    Maybe the molecular biologists should have spent more time reading up on population genetics?

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  2. Off topic: I hope you've not forgotten to let us know the total length of all the DNA in the biosphere? I'd dearly love to know the answer and to see how spectacularly wrong my own estimate was.

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    1. According to Michael Lynch, it's about 10^25 km or 10^12 light years or 10 times the diameter of the known universe.

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  3. We know that about 90% of our genome is junk.

    If I remember correctly (I may not), about 2.5-3% is "known functional." That leaves 7-7.5% that may or may not be junk. Are there any general characteristics common to this 7-7.5%, or is it made up of all sorts of different stuff? Or do I just have this all wrong?

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    1. Here's a recent study that suggested about 8% of the human genome is constrained by purifying selection (and therefore presumably functional):

      http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004525

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    2. Thanks Larry -

      Any further breakdown on what's in the functional 2% conserved intergenic not otherwise identified?

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  4. There are probably stretches of DNA that code for RNAs that do not go on to make proteins.

    I was initially shocked to learn that Collins had only recently learned about ribosomal and transfer RNAs, but then I realized that they both do go on to make proteins. Assuming that's what he meant.

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    1. It means that he was unaware of the genes for the spliceosomal RNAs and even unaware of 7SL RNA or the RNA component of RNAse P. Sidney Altman got a Nobel Prize in 1989 for discovering the RNA in RNAse P. Maybe Francis Collins was too busy looking at waterfalls back then.

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    2. No, it means more than that. It means, apparently, that he wasn't aware of 28s rRNA or 12s rRNA or tRNA-Cys or tRNA-Met, and so on. Those have genes, right? OK, he clearly must have been aware of them; you can't be a molecular biologist without knowing what ribosomes are and how translation works. So I really don't know what he could have been thinking. My post was a joke.

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  5. It also astonishes me that scientists in the 21st century could still have been defining a gene as "a stretch of DNA that codes for a particular protein.

    But surely it's a better generalization than the opposite misconception, that every transcript is a gene. RNA genes are fascinating, but the number that have been shown to really have biological function are a tiny fraction of those of protein coding genes.

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    1. What Is a Gene?

      A gene is a DNA sequence that is transcribed to produce a functional product.

      Not perfect but far, far better than assuming that the pieces of DNA that make ribosomal RNA and tRNA don't count as genes.

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    2. Considering how deoxyRibozymes have been discovered (although they were synthetic), I would not be surprised if it was eventually discovered in some species that some tare stretches of DNA merely need to be copied and can then fold into functional products without even being transcribed to RNA.

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  6. Larry Moran: "It astonishes me that scientists working on the human genome were not aware of the scientific literature on the number of genes in the human genome."

    So according to Larry's standard conclusion these persons don't understand the discipline or evolutionary theory.

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    1. No Ray, the 30,000 figure was published decades before in the population genetics literature. Do you dispute that?

      Collins, and many muggle reporters, said 100,000 genes for no scientific reason. They were unfamiliar with the population genetics literature, and as chauvinistic humans, they wanted to be more complex than fruit flies. Those are not scientific reasons for pulling the number 100,000 out of their asses.

      They were ignorant of population genetics at a bare minimum; arguably also neutral theory.

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    2. The largest guesstimate I've ever seen was "2 million genes" in the human genome (Günther Witzany 1997). Witzany provides no reference, so his source remains unknown. But then perhaps Witzany is not a real person but a pseudonym used by Alan Sokal.

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    3. No, Ray, what Larry meant was that he was astonished that scientists working on the human genome were not aware of the scientific literature on the number of genes in the human genome.

      Generally, when one embarks on a project in science, one gets familiar with the existing body of scientific literature relevant to that project.

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  7. Larry is the only one who understands evolutionary science.

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  8. Larry, you're very patient at deconstructing these things, but the best description of Francis Collins' writing comes from Ross on the show Friends:

    Ross: You know how you throw your jacket on a chair at the end of the day?

    Joey: Yeah...

    Ross: Well, like that, only that instead of a chair it's a pile of garbage. And instead of a jacket it's a pile of garbage. And instead of the end of the day it's the end of time, and garbage is all that has survived.

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  9. Larry says: It turned out that there were large stretches of highly repetitive DNA, just as expected.

    Does anyone have a 3D chromosome territory map or schematic diagram showing what these large stretches of highly repetitive DNA (after replication) uncoil to become?

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  10. @Larry,

    "I've been doing a bit of research on the human genome in preparation for a book."

    I don't think anybody has the wildest idea what the book is going to be about.

    Can you at least let everyone know what it is going to be called?

    How about this: "Human genome is still mostly junk-90% down from 98%"

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    1. Could you please give me a citation of a paper where a biologist claimed that 98% of the human genome was junk?

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    2. Let's put it this way:

      As for as you know, when was the first function (s) first assigned to the non-coding part of human genome?

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    3. Could you please give me a citation of a paper where a biologist claimed that 98% of the human genome was junk?

      My guess is liesforthedevil is confusing this with the claim that the human and chimp genomes could be 98% similar. But who really knows why he's confused? Or cares?

      That was a great answer you gave to Dave's question, BTW, liesforthedevil. Do you not understand what a "citation" is?

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    4. All biology textbooks to date...

      I own and have read a number of biology textbooks. I don't recall every reading the claim that 98% of the human genome was junk. If you think that this is a very common claim, please provide at least one or two specific examples of this.

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    5. "All biology textbooks to date..."

      I have read a couple of biology textbooks, and tons and tons of references, popular press articles, educational sources and so on.

      I have never ever even once come across a claim that 98% of the human genome is junk.

      Like lutesuite says, I think you guys are confusing the estimation of THE SIMILARITY BETWEEN THE HUMAN AND CHIMP GENOMES with the fraction of the genome estimated to be junk.

      How similar the human genome is to the chimp genome =/= the amount of junk in the human genome.

      Truly, you creationist types are borderline dyslexic when it comes to evolution and biology literature.

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    6. Actually, I think they're confusing "2% protein-coding sequences" with "2% functional", as if there were no functional RNAs or regulatory sequences known.

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    7. John,

      Have you ever came across the claim that 98% of human genome could possibly be junk because there was no assigned function to it yet? I'm talking in he old days

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    8. It's funny how Dave changed his attitude from "show me the money" to " I don't recall".

      I'm sure when presented with evidence he will use one of Larry's escape trick such as '" no knowledgeable scientist thought 98% of human genome was junk".

      And the Darwinian carousel keeps on spinning

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    9. Mikkel,

      Thank God no knowledgeable university uses Larry's text books or all of them would be infected with the bias and propaganda about junk DNA.

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    10. It's funny how Dave changed his attitude from "show me the money" to " I don't recall".

      I'm sure when presented with evidence he will use one of Larry's escape trick such as '" no knowledgeable scientist thought 98% of human genome was junk".

      And the Darwinian carousel keeps on spinning


      While I'm happy that you find me amusing, I'm afraid I must remind you that the only claim I have made here is that I have not personally ever seen a biologist state that 98% of the genome is junk. I would be happy to revise that claim if somebody would provide examples where a biologist does this. I'm still waiting...

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    11. This is Darwinian bs. You are just another ignorant SH who has selective memory loss.
      Do you know how to google?

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    12. Have you ever came across the claim that 98% of human genome could possibly be junk because there was no assigned function to it yet? I'm talking in he old days

      No.

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    13. I googled, as Lies suggested. I found many statements that 98% of the genome is junk. But all of them were made as strawman claims to argue against, and never attributed to any particular person. That is, the only people saying that 98% of the genome is junk were people who wanted to claim that there's no junk.

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    14. Exactly. There are no claims in the peer-reviewed literature that 98% of the genome is junk because we don't know its' function. We've all argued with creationists about this for years, we demand the citations, they don't cough them up.

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    15. Hey liesforthedevil,

      When will you give me that list of your "scientist friends"?

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    16. lftd I'm sure when presented with evidence he will use one of Larry's escape trick such as '" no knowledgeable scientist thought 98% of human genome was junk"

      Now, how can we possibly put that theory to the test ... ?

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    17. Allan that looks more like a hypothesis (an idea you can test) to me.

      I tested it using Google Scholar.

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    18. Gary, when you tested it, what was the result?

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    19. John Hirschman,

      I googled, as Lies suggested. I found many statements that 98% of the genome is junk. But all of them were made as strawman claims to argue against, and never attributed to any particular person. That is, the only people saying that 98% of the genome is junk were people who wanted to claim that there's no junk.

      So you did find some information that 98% of human genome being junk was claimed you just don't like that it was never attributed to one person or as Larry would put it: " no knowledgeable scientist would make such a claim."

      You see John, the ten famous icons of evolution were never attributed to one person including the Muller-Urey experiment. Not the actual results that supposedly their experiment resolved like the problem with the origins of life. But it was being sold as such.

      You see John, in the world of lies for devil it is not the proof or disproof you have that matters. It is how you sell it.

      Arnold Swarzenegger once said that you can sell even the worst possible product if you just know how to do it.

      He was referring to himself as not having any acting abilities and speaking with the heavy German accent.

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    20. John Harshman,

      What I would really like to see from you and the followers of devil is how the mechanism of the evolution works especially including the random genetic drift. I know you have been married to this, so explain how it works and why Coyne is not buying it. Why he is against it?

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    21. Gary, when you tested it, what was the result?

      It tested true, but it was also true that many who repeated the claim were arguing against that possibility.

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    22. so explain how it works and why Coyne is not buying it. Why he is against it?

      How it works, from a fisheries bureau:

      Genetic drift is random changes in gene frequency that occur because of sampling error. Sampling error can be natural, or it can be manmade. Natural sampling errors are those which occur when earthquakes, floods, landslides, or other natural disasters subdivide a population and isolate small groups of organisms. This process is a major force in the evolution of new species.

      What Coyne thinks: He's not "against it," since plainly random stuff happens, so he'd very likely agree with the first part of the quote above. He might not agree with the last sentence - he might not feel drift should be assigned such a major (direct) role in evolution of new species. By "direct" I mean that it is plain drift opens up new evolutionary pathways, but Coyne may feel it is not directly responsible for the changes at the end of the pathway where a new species emerges.

      (I'm a layperson, so the foregoing may have mistakes, for which I am solely responsible.)

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    23. It tested true, but it was also true that many who repeated the claim were arguing against that possibility.

      Did you find anyone at all arguing in favor of the claim? I didn't.

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    24. I found that fisheries bureau description of drift to be mighty poor. What they describe isn't drift; it's founder effect. Founder effect is a form of drift but by no means the typical case. Sampling error happens in every generation in every finite population, simply because that population doesn't perfectly reproduce the exact frequency of every allele from parent generation to offspring generation.

      Now, what Coyne thinks of drift is simple: it fixes alleles at a much slower rate than selection, so that speciation due entirely to drift will happen much more slowly than speciation due to selection. And while two populations wait to become incompatible through drift, it's fairly likely that isolation will arise as a byproduct of selection, and thus speciation by drift will seldom happen. Note that here we're talking about plain vanilla allopatric speciation, in which both geographically separated populations are of reasonable size, not tiny peripheral isolates.

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    25. So you did find some information that 98% of human genome being junk was claimed you just don't like that it was never attributed to one person or as Larry would put it: " no knowledgeable scientist would make such a claim."

      No, I'm afraid you can't read. I found nobody making the claim that 98% of the genome is junk. I found only people (like you) making the claim that somebody else, always unspecified, thinks that 98% of the genome is junk. This is the equivalent of the urban legend, the sort of thing that always happens to a "friend of a friend" but never to anyone real. You have nothing.

      What I would really like to see from you and the followers of devil is how the mechanism of the evolution works especially including the random genetic drift. I know you have been married to this, so explain how it works and why Coyne is not buying it. Why he is against it?

      Short answer: he isn't against it, and I have no idea where you got that notion. I see no need to explain to you how evolution works; it's a big subject, and you can always read a text if you want. If you were actually interested in learning I might be more forthcoming, but you have displayed your pride in ignorance too many times here.

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    26. Did you find anyone at all arguing in favor of the claim? I didn't.

      No, I could not find anyone arguing in favor of it either. It was more like there were a small number of experienced scientists who cautiously accepted the 98% figure, in which case they believed it was possibly true. But they were not well enough convinced for it to be an issue worth arguing over.

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    27. I say again: can you find anyone making the claim, however tentatively, that 98% of the human genome is junk? If so, who is that person?

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    28. Hi John, would like to know a little more about what this means if you would be kind enough to explain:

      it's fairly likely that isolation will arise as a byproduct of selection

      An example (doesn't need to be actual) would likely do.

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    29. No, I could not find anyone arguing in favor of it either. It was more like there were a small number of experienced scientists who cautiously accepted the 98% figure, in which case they believed it was possibly true. But they were not well enough convinced for it to be an issue worth arguing over.

      Hmm. When I attempted to replicate your study, I was not able to find any scientist claiming that 98% of the human genome is junk, not even at the level of "cautiously accept(ing)" that "it was possibly true." . I did find websites from the likes of TIME, FoxNews, and catholic.org that repeated the claim that 98% of the genome is non-coding, and who confused this with "junk". But obviously you would have rejected this data as irrelevant to the question being investigated. Right?

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    30. judmarc,

      If there's a central message of Coyne & Orr's book Speciation, that's it. If two populations of the same species are geographically isolated from each other, they are likely to experience somewhat different selective environments. In the lab, populations under different selective regimes tend to evolve partial reproductive isolation. The selection isn't directed at isolation but at other characters, and the isolation arrives as an incidental product of selection for other things. You could explain that by pleiotropy, hitchhiking, or perhaps something else, but that's the observation. For examples (and for much else) I recommend the book.

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    31. If two populations of the same species are geographically isolated from each other, they are likely to experience somewhat different selective environments.

      The reference to "two populations" is the part I somehow glossed over in your original comment. I was therefore trying to figure out how reproductive isolation would arise as a byproduct of selection in the absence of geographic barriers. (I figured this could happen, but very rarely relative to the situation where two or more populations are geographically separated.)

      You've recommended the book before, and believe me, I've taken note. I'd prefer for a Kindle edition to become available, though. :-)

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    32. Here is how the lies for the devil work.

      Nobody has ever been attributed in person by the "98% of Your DNA is Junk" but all over the lies are being repeated:

      "98% of Your DNA is Junk"

      The Race Is Over
      The great genome quest is officially a tie, thanks to a round of pizza diplomacy. Yet lead researcher Craig Venter still draws few cheers from his colleagues


      "Junk. Barren. Non-functioning. Dark matter. That’s how scientists had described the 98% of human genome that lies between our 21,000 genes, ever since our DNA was first sequenced about a decade ago. The disappointment in those descriptors was intentional and palpable.

      It had been believed that the human genome — the underpinnings of the blueprint for the talking, empire-building, socially evolved species that we are — would be stuffed with sophisticated genes, coding for critical proteins of unparalleled complexity. But when all was said and done, and the Human Genome Project finally determined the entire sequence of our DNA in 2001, researchers found that the 3 billion base pairs that comprised our mere 21,000 genes made up a paltry 2% of the entire genome. The rest, geneticists acknowledged with unconcealed embarrassment, was an apparent biological wasteland."

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    33. the 3 billion base pairs that comprised our mere 21,000 genes made up a paltry 2% of the entire genome

      Cite a scientific publication, not an incompetent journalist who doesn't even seem to know that 3 billion bp is the approximate total length of the human genome (2% of that is only 60 million bp). She stupidly repeats an urban myth, which is just what incompetent science reporters do.

      What geneticists ever said what she claims they said? Names and references, please.

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    34. Ha! You found something. It's fairly old (published in 1992) and pretty obscure (only cited 6 times since 1992), but I think it qualifies. Well done!

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    35. It's a claim by a medical ethicist, not a biologist. But at least it's an actual claim. Better than nothing, but not much better.

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    36. The author is not a geneticist, biochemist or anything of the sort, and the book is not about genetics. No source is offered for the "98% junk" claim, there's no bibliographical reference to back it up. So here's just another non-specialist spreading an urban myth. By the way, Shenkin estimates that "only" about 500 million bp are "truly informative", and that they account for less than 2% of the human genome. If that were true, the total length of the human genome would be at least 25 billion bp. I don't think he did his homework well before writing that chapter.

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  11. This is Darwinian bs. You are just another ignorant SH who has selective memory loss.
    Do you know how to google?


    So I take it that you will not be providing evidence to back up your statement. Fair enough. This has been an...illuminating exchange.

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    1. Dave,

      I'm still waiting for you answer.:

      "As for as you know, when was the first function (s) first assigned to the non-coding part of human genome?

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    2. I'll answer. So far as I know, the first function assigned to non-coding DNA were regulatory elements discovered by Jacques Monod and Francois Jacob circa 1965 based on work done in the 50's.

      Now you can answer my questions.

      1. Please list these "scientist friends" you speak of. Who are they?

      2. Since you say the Central Dogma has been falsified, please list the reverse genetic code by which amino acid sequences are translated into genetic sequences.

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    3. 1.My friends are the very knowledgeable scientist who think you are just another (?) you fill in.

      2. Why would you add another layer to the complexity to your already weak, weak assumptions? Don't you get it? You've lost. You had lost before this issue. Why would someone like you do it? Give me one really good reason and I will leave you alone.

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    4. "Don't you get it? You've lost. "

      Where did Diogenes lose? Where has the Central Dogma been falsified?

      Let's assume it has been falsified. What do you think this means for the field of evolution?

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    5. "1.My friends are the very knowledgeable scientist who think you are just another (?) you fill in."

      Hahahahaha. I laughed for like a whole 20 seconds. Ohmyjebus...

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  12. Alternative splicing doesn't just create more than one protein per gene but creates protein isoforms. It is just one of many mechanisms that generate isoforms and there could be billions if not trillions of these isoforms.

    There are other isoform generation mechanisms than Alternative Splicing such as V(D)J recombination that is known to have the potential to create billions if not trillions of isoforms. No one thinks those isoforms are spurious just because they get trashed, the trashing process is part of the computation for adaptive immune response.

    What defines spurious is in the eye of the beholder and beholders who insist something is junk just because it eventually is trashed should consider programmed cell death and apoptosis.

    No one knows all the roles of isoforms generated by all the isoform generating mechanisms (such as alternative splicing, V(D)J recombination, post transcription editing, post translational modification, etc.). Our high throughput techniques can hardly catalogue even a fraction of them.

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    1. "No one knows all the roles of isoforms generated by all the isoform generating mechanisms"

      Actually, with V(D)J recombination, we know a lot about its role: it is how antibodies are made. During B-cell production, the V, D, and J units coding for immunoglobulins are randomly spliced together, so that B-cells each carry an antibody with a different specificity. So that explains alternative splicing in one gene.

      Another interesting aspect of this is how antibody production recapitulates evolution by natural selection. When a B cell first encounters a foreign antigen it can bind to, it is activated and begins to divide rapidly. These cells then undergo affinity maturation, it which random mutations are introduced into the binding site of the antibody, generating a large pool of genetic variation. Forms which bind the antigen less efficiently or lose the ability to bind the antigen no longer receive the proliferation signal and soon get selected out of the B cell population. Forms which bind better continue to receive activation signal and continue to proliferate, increasing in frequency.

      So by random mutation and non-random selection for better binding variants, antibodies with an increased affinity for the antigen are evolved. Pretty cool, isn't it?

      Also, it proves wrong the hypothesis put forward by many creationists, notably including Behe, that random mutation cannot create better protein binding domains, but only break them. This is proven wrong billions of times every day across the Earth.

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